One-third of individuals over the age of 20 in the United States have hypertension. High blood pressure is a major risk factor for coronary heart disease and stroke. The estimated burden of the effects of hypertension in the U.S. during 2010 was estimated to be $93.5 billion due to health care costs and missed work. The causes of the onset and the progressive increase in blood pressure over time are not known for most cases of hypertension. In recent studies in rats we have discovered that initial challenges with low, non-pressor doses of either angiotensin II or aldosterone wilf sensitize the pressor response to subsequent hypertension-inducing stimuli. Additional evidence indicates that these sensitized pressor responses are a result of sustained changes in the central nervous system. Similar types of neuroplasticity have been observed and studied in neural networks controlling many behavioral and physiological response systems. However, as of the present time, there has been little appreciation of the role that changes in information processing in the nervous system as a result of experience-induced sensitization may have in the pathogenesis of hypertension. Therefore, the principal hypothesis to be tested in this proposal is that physiological and environmental challenges act to sensitize the pressor response to hypertension-inducing stimuli by inducing neuroplasticity within specific components of the brain's neural network controlling blood pressure. An important corollary of this hypothesis to be tested in that components of the brain renin-angiotensin-aldosterone system act in conjunction with other neuroplasticity-associated signaling systems to produce long-term modifications of the brain and a sensitized hypertensive response. To address an evaluation of these hypotheses, three specific aims will be pursued that will employ functional, cellular and molecular methodologies to analyze where in the central nervous system and in what cell types neuroplasticity occurs to effect sensitization of hypertension. The results of these studies will provide important new information and insights into the pathogenesis of high blood pressure. RELEVANCE (See Instructions): The nervous system plays a major role in the regulation of blood pressure and has the capacity to adjust cardiovascular function over the course of time through the processes involving neuroplasticity. Understanding how physiological or exogenous stimuli, present earlier in life, can modify brain function to produce a predisposition for an enhanced hypertension to a subsequent cardiovascular challenge is likely to identify targets and strategies for intervening in the pathogenesis of high blood pressure.